This is an application for a K08 mentored career development award for Dr. Jonathan Li, an Instructor in Medicine at Harvard Medical School and the Brigham and Women's Hospital. Dr. Li is a physician-scientist committed to a career in translational HIV research. He has gathered an experienced team of mentors, collaborators, and advisors and is proposing a comprehensive research, course work, and career development plan that will position him to be a successful independent investigator. The overall goal of Dr. Li's proposed research is to determine the effect of HIV-1 minority variants on the risk of antiretroviral treatment failure and to use minority variant populations to improve our understanding of HIV reservoirs. HIV exists as a diverse cloud of viruses within each infected individual, but current commercial HIV-1 drug resistance tests only take into account mutations present in at least 15-25% of the viral population. However, in a recently published analysis by Dr. Li, minority HIV-1 drug resistance mutations present below the limit of detection of commercial resistance genotyping tests can increase the risk of NNRTI-based therapy failure by more than two-fold. This K08 proposal builds upon these important findings. The main aims are to 1) Determine the prevalence and clinical impact of drug-resistant minority variants within the HIV DNA reservoir; 2) Evaluate the effect of minority integrase inhibitor resistance mutations on the risk of treatment failure; and 3) Characterize fluctuations in HIV-1 RNA and DNA population dynamics in patients with chronic, untreated HIV infection. The knowledge gained from these studies could improve our ability to choose the best treatment regimen for each patient and may help guide strategies for eradicating the HIV reservoir.